This application requests support for a Keystone Symposia meeting entitled Innate Immunity: Sensing the Microbes and Damage Signals, organized by Gabriel Nunez and Akiko Iwasaki, which will be held in Keystone, Colorado from March 4 - 9, 2012. In recent years there have been major advances in our understanding of the mechanisms that are involved in the recognition of microbes and subsequent activation of host immune defenses. Several classes of membrane-bound and cytosolic pattern recognition receptors (PRRs) have been identified and partially characterized. These include the Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Activation of PRRs leads to the production of a large array of pro- inflammatory and anti-microbial molecules that are critical for the elimination of invading pathogens, and activation of adaptive immune responses. A class of cytosolic PRRs is involved in the assembly of the inflammasome, a molecular platform that mediates activation of caspase-1 and secretion of mature IL-1beta and IL-18. Importantly, activation of the inflammasome is also induced by non-microbial mechanisms including endogenous molecules involved in the pathogenesis of metabolic and inflammatory diseases. In addition, there is evidence that autophagy, a cellular process that mediates recycling of intracellular components, is involved in microbial recognition and plays a key role in host defense. The initial sensing of microbes often occurs at mucosal surfaces, but the interplay between recognition of commensal vs. pathogenic microbes on the host immune system is only beginning to be uncovered. The goal of the Keystone Symposia meeting on Innate Immunity: Sensing the Microbes and Damage Signals is to gather scientists working on innate immunity to discuss cutting edge research on the mechanisms that regulate the activation of the immune system by microbes as well as by endogenous damage signals, and to integrate such knowledge in the context of inflammation, homeostasis, host defense, and disease. Opportunities for interdisciplinary interactions will be significantly enhanced by the concurrent meeting on The Microbiome, which will share a keynote address and three plenary sessions with this meeting. PUBLIC HEALTH RELEVANCE: The innate immune system recognizes pathogens (disease-producing agents) through pattern recognition receptors (PRRs) and induces the activation of the adaptive immune system. Dysregulation in innate signals leads to inflammation and manifests in various diseases and disorders including cancer, autoimmunity, allergy, and inflammatory diseases. Basic understanding of the mechanisms by which PRRs sense pathogens and then signal to elicit appropriate immune responses is critical in vaccine design and immunotherapy of inflammatory diseases. The Keystone Symposia meeting on Innate Immunity: Sensing the Microbes and Damage Signals, in combination with a concurrent meeting on The Microbiome, will provide a unique environment to foster intellectual exchange and collaboration between scientists who focus on diverse aspects of the innate immune system.